Project summary Acute pancreatitis is among the most common gastrointestinal causes for hospitalization in the U.S. Roughly one in five patients with acute pancreatitis will have recurrent bouts. Recurrent acute pancreatitis (RAP) is a strong risk factor for progression to chronic pancreatitis, an irreversible fibroinflammatory disease that greatly impacts quality of life, and is also a risk factor for pancreatic cancer. Increased intraductal pressure is an accepted cause for precipitating an episode of acute pancreatitis. Pancreas divisum, seen in 7-10% of the general population, occurs when the dorsal and ventral pancreatic ducts have incomplete or nonexistent fusion during early embryologic development. Using this rationale, endoscopists often perform endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla sphincterotomy (miES) in patients who have idiopathic RAP (iRAP) and pancreas divisum with a goal to reduce subsequent attack(s). This practice remains highly controversial, due to major limitations in the available data which are derived almost exclusively from small, retrospective cohort studies with inconsistent and subjective outcomes. This is one of the highest risk indications for ERCP, having post-ERCP pancreatitis rates of 10-20%. A full scale, well-designed clinical trial with adequate follow-up and blinded treatment allocation is clearly needed to empirically evaluate the efficacy of miES in the setting of iRAP and pancreas divisum, including quantifying the cumulative benefit of this intervention on disease burden and to study its relationship with its natural history. Capitalizing on the existing infrastructure of the recently completed EPISOD trial and NAPS2, we propose a sham-controlled, single blind with a blinded outcome assessment, randomized trial evaluating the impact of miES on the natural history of iRAP in patients with pancreas divisum. The primary outcome is reducing the risk of subsequent acute pancreatitis (time-to-event), with secondary outcome measures being the change in density of attacks, patient-centered outcomes, and progression to chronic pancreatitis. By having an adequate sample size to measure the benefit of ERCP, we will be able to definitively establish the therapeutic role of ERCP in patients with iRAP and pancreas divisum. A biorepository will be established for future exploratory studies of novel risk factors for recurrent acute pancreatitis, progression to chronic pancreatitis and its sequelae, and factors associated with response to miES. Patients fulfilling the entry criteria but refusing enrollment into the randomized trial will be enrolled into an observational cohort. Irrespective of the outcome, this study will have an immediate impact on patient care by confirming or refuting the therapeutic role of ERCP in patients with iRAP and pancreas divisum.